Successful application of potential neuroprotective agents will depend on early detection of neurodegenerative diseases. Biochemical and cellular processes that trigger and accompany the neuronal loss in these diseases are known to be active for years prior to irreversible structural changes and diagnosis. The long-term goal of this work is to establish non-invasive, quantitative magnetic resonance spectroscopy (MRS) measures sensitive to the cellular and biochemical processes associated with the progressive neuron loss in neurodegenerative diseases and to utilize these measures in early detection and management of disease. This application focuses on two processes common to many neurodegenerative diseases, gliosis and oxidative stress. Hereditary ataxias with known involvement of gliosis or oxidative stress were chosen as the test case to establish the utility of MRS. In Specific Aim 1, indicators of gliosis (myo-inositol and glutamine) will be quantified by high field (4 tesla) MRS in cerebella and pons of patients with spinocerebellar ataxias SCA2 and SCA6 in comparison to healthy controls. Associations will be sought between these MRS markers and glial fibrillary acidic protein levels in cerebrospinal fluid (CSF) as determined by ELISA as an independent measure of reactive gliosis. Additionally, cerebellar and pons atrophy will be assessed by three-dimensional (3D) MRI and clinical severity by a quantitative ataxia rating scale. In Specific Aim 2, indicators of oxidative stress (glutathione and vitamin C) will be quantified by high field MRS in cerebella and pons of patients with Friedreich's ataxia (FRDA) in comparison to healthy controls. Associations will be sought between these MRS markers and F2-isoprostane levels in CSF as measured by GC/MS as an independent measure of oxidative damage in the brain. Cerebellar and pons atrophy will be assessed by 3D MRI and clinical severity by a quantitative ataxia rating scale. In both aims, the goal is to validate the non-invasive MRS measures with more established, but invasive CSF biomarkers. The MRS measures are expected to correlate with the CSF and clinical severity measures. In Specific Aim 3, neurochemical profiles of cerebella and pons of asymptomatic carriers of SCA2 and SCA6 will be measured by high field MRS and compared to those of healthy controls. This aim will start addressing the long term goal of early detection. It is expected that pre-clinical biochemical abnormalities associated with neuron loss will be detected in these individuals. Reliable in vivo quantitation of biomarkers in the intact brain will have a high impact in the management (early detection, disease staging and treatment monitoring) of many common neurodegenerative diseases. RELEVANCE: This work intends to establish non-invasive, quantitative imaging measures of biochemical and cellular alterations in neurodegenerative diseases. Such measures can eventually be used in the clinic for early disease detection, which in turn will facilitate application of treatments to delay the onset of these diseases, as well as for monitoring treatment response. Successful application of such treatments is expected to reduce the burden caused by these diseases on individuals, their families and society.